Are You Confident of the Diagnosis?

This was first described in a publication by D’Angio in1959 describing radiation recall associated with actinomycin D. Radiation recall phenomenon is well recognized, but the pathophysiology is poorly understood. Infrequently seen clinically and usually associated with the skin, the reaction can also occur in other organs such as the lung, bowel, muscle, and esophagus. The phenomenon has most commonly been associated with cytotoxic chemotherapy, but has also been described with a variety of medications such as antibiotics, antituberculous medications, and other medications such as Simvistatin and Tamoxifen.

What you should be alert for in the history

One should suspect radiation recall if a patient presents with a skin reaction similar in appearance to acute radiation dermatitis with clearly defined edges that correspond to the patient’s previously irradiated field. There are reports in the literature describing progression of the in-field skin reaction to a more generalized skin change extending outside the initial field of involvement.

Characteristic findings on physical examination

The presence of the reaction in association with the prior radiation field can be determined by inspection of the patient’s skin for permanent tattoos delineating the radiation field. With modern radiotherapy techniques used for head and neck radiotherapy, which include immobilization with “masks”, skin tattoos may be absent altogether. In all cases of suspected radiation recall dermatitis, a discussion with the patient’s treating Radiation Oncologist should occur, as this can assist in verification of the prior radiotherapy portal(s). The skin findings may clinically range from a mild maculopapular erythematous rash to severe skin necrosis.

Grade 1 dermatitis most consistent with radiation recall within a palliative hip/femur field following initiation of systemic chemotherapy. Reaction has clearly demarcated border conforming to radiotherapy field (Figure 1).

Figure 1.

Radiation recall in palliative hip/femur field following initiation of chemotherapy.

Expected results of diagnostic studies

Due to the relatively infrequent occurrence of this phenomenon, the incidence of radiation recall reaction in general and with specific agents is not well characterized.

Diagnosis confirmation

Who is at Risk for Developing this Disease?

Patients must have received prior radiotherapy to qualify for a subsequent diagnosis of radiation recall. The exposure and reaction must occur after completion of radiotherapy and resolution of any acute radiation dermatitis. Radiation dermatitis during the primary course of radiotherapy is not required to meet criteria for the subsequent diagnosis of radiation recall.

The severity of the reaction is extremely variable and may develop in patients who experienced no clinical evidence of acute radiation dermatitis with their initial radiation. The recall phenomenon can also involve one prior radiotherapy field while leaving other previously irradiated fields unaffected.

Doses of radiation reported in association with recall dermatitis range from 10Gy to 80+Gy, failing to support the notion of a “threshold” dose. In addition, there are no data supporting a specific relationship with dose per fraction or fractionation scheme.

For radiation dermatitis occurring with the delivery of chemotherapy within 10 days of completion of a radiation course, this is generally considered sensitization rather than true radiation recall due to the temporal relationship of the two therapies. This notion is also supported in the literature. The literature also suggests that a factor related to the potential increased severity of the reaction is a short interval from completion of radiation to exposure to the offending agent. Upon review of the literature, medications reported to be associated with radiation recall dermatitis include (listed in alphabetical order):

Actinomycin D

Adriamycin

Bleomycin

Capecitabine

Cytarabine

Cyclophosphamide

Dacarbazine

Docetaxel

Edatrexate

Erlotinib

Etoposide

5-Fluorouracil

Gemcitabine

Hydroxyurea

Interferon α-2b

Lomustine

Melphalan

Mercaptopurine

Methotrexate

Nimesulide (not available in US due to hepatotoxicity, but available extensively worldwide)

Oxaliplatin

Paclitaxel

Simvistatin

Sorafenib

Sunitinib

Tamoxifen

Trastuzumab

Trimetrexate

Tuberculosis Therapy (isoniazid/rifampicin/pyrazinamide/pyridoxine)

Vinblastine

Nearly 50% of all reported radiation recall reactions in the literature are associated with taxanes and/or anthracyclines. For objective categorization of radiation recall dermatitis, the National Cancer Institute CTCAE version 3 acute skin scoring system is utilized.

Skin necrosis or ulceration of full-thickness dermis; may include bleeding not induced by minor trauma or abrasion

Radiation recall dermatitis onset generally occurs with the first dose of the inciting agent, however, the time course for the development of the reactions reported in the literature is extremely variable. Most reactions are reported to occur within hours to weeks of exposure to the medication; however, are reports in the literature of reactions delayed months to years following drug exposure. Case reports in the literature also suggest that the reaction is drug dependent due to the fact that other cytotoxic drugs, including those for which there are literature reports of radiation recall association, can successfully be delivered despite a history of radiation recall reaction.

What is the Cause of the Disease?

Pathophysiology

The precise etiology of this phenomenon is not fully characterized. A review of the literature outlines several proposed pathways for the development of radiation recall dermatitis:

Recall based on radiation effects in cells which survived prior exposure

This is proposed to be due to the “remembered” reaction of cells surviving the initial radiation exposure, or that these cells carry defects induced by the initial course of radiation that are passed on through descendants resulting in the reaction. The variable degree of response and lack of correlation with prior radiation parameters, including severity of prior acute radiation dermatitis, appears inconsistent with this potential mechanism. In addition, the literature supports the capacity of these cells for repair.

Stem cell dysfunction

Therapeutic radiation has known capacity to result in stem cell dysfunction and loss, contributing to the development of acute radiation dermatitis. The subsequent exposure to the cytotoxic chemotherapy then results in further damage to cells predisposed to injury by prior exposure. This hypothesis is not consistent with the association of drugs other than cytotoxic chemotherapy with this phenomenon. In addition, repeat exposure to the offending drug, although not uniformly performed, did not consistently result in equivalent or increased response. The rapidity of the potential recall reaction also appears inconsistent with this hypothesis.

Vascular

Acute radiation dermatitis is known to result in endothelial cell damage, however, following recovery this appears to resolve, resulting in normal appearance and function of the skin. Therefore, it appears unlikely that exposure to the related drug would result in rapid alteration in function and permeability to cause the recall reaction.

Drug reaction

Some data suggest that the phenomenon is mediated by a drug hypersensitivity-like reaction. The theory suggests that the potential for a non-autoimmune inflammatory response has been increased in patients with prior exposure to radiation therapy. Following recovery from the acute radiation-induced inflammatory reaction, these cells may continue to secrete cytokines which are then increased by the exposure to the subsequent agent, resulting in the clinical characteristics of radiation recall.

Histology

It is important to exclude recurrent malignancy within the differential diagnosis. Histopathological confirmation may be required and should be performed if the risk:benefit ratio warrants a biopsy due to clinical suspicion of recurrence.

Often, the clinical presentation of clear linear margins of skin reaction are inconsistent with tumor recurrence and do not, therefore, require a biopsy unless persistent despite the withdrawal of the offending agent. When a biopsy is obtained, the findings commonly include atypia with vascular dilatation in the dermis in association with necrotic keratinocytes. Authors have also reported the presence of increased mitotic figures within a background of inflammatory cells.

Treatment Options

The primary treatment modality is cessation of the related medication. In many instances, the improvement occurs rapidly following discontinuation of the offending agent.

If therapy is required, steroids are a mainstay and can be delivered topically, orally or intravenously, depending upon the severity of the reaction, organ system involved, and clinical presentation. Case reports also have outlined the use of non-steroidal anti-inflammatory agents or antihistamines in the management of radiation recall.

Other than withdrawal of offending agent, there is no additional therapy proven to shorten the time to recovery. In view of the fact that the clinical presentation is a skin reaction similar to acute radiation dermatitis, symptomatic relief may also be noted with management options used to treat acute radiation dermatitis of similar severity.

Generally, the patient is not re-challenged with the involved drug, however, if clinically warranted for management of the malignancy, reduced dose and/or concurrent steroid therapy has been reported. The time for resolution of the skin changes ranges from hours to weeks and appears to be dependent upon the route of delivery of the offending agent as well as the drug pharmacokinetics.

Optimal Therapeutic Approach for this Disease

Discontinue associated agent

If agent is considered therapeutically imperative, rechallenge can be considered

If rechallenged with offending agent, dose reduction and/or concurrent use of steroid therapy should be considered

If offending agent not clinically imperative, consideration of an additional systemic chemotherapy should be entertained

No evidence that alternative agent in same drug class or alternative agent also known to be associated with radiation recall is contraindicated in patients experiencing recall dermatitis

Consider biopsy-histology can be consistent with radiation recall or suggestive of an alternative diagnosis

Patient Management

During the active phase of the recall reaction, patients should be monitored on at least a weekly basis to asses for ongoing resolution of the symptomatology as well as other complicating factors such as infection.

Following resolution, the skin within the affected area does not appear to exhibit increased late effects such as fibrosis or atrophy, as is potentially noted following acute radiation dermatitis.

If the symptoms fail to resolve in a manner consistent with radiation recall (provided the offending agent can and has been withdrawn) then an alternative diagnosis should be considered. Determination of additional management should also include ongoing discussion with the patient’s treating Hematologist, Oncologist and Radiation Oncologist.

For recall reactions involving the breast, MRI imaging may be helpful in evaluating the enhancement pattern for potential characteristics suggestive of tumor recurrence.

Unusual Clinical Scenarios to Consider in Patient Management

In the event that a clinician is faced with a clinical presentation that appears most consistent with radiation recall reaction yet the subsequent clinical course of the patient appears inconsistent, additional evaluation is required. At that juncture, consideration of a biopsy should be entertained, particularly if there is any increased clinical suspicion of recurrent malignancy. As noted in the differential of acute radiation dermatitis, the differential diagnosis can be quite broad and should include:

Contact dermatitis - usually can be differentiated from radiation dermatitis by skin distribution. Contact dermatitis rarely is limited to only the radiation field, as is seen in radiation dermatitis, unless associated with allergy to skin product(s) being used to treat the skin during therapy, ink used for the tattoo process during radiation therapy, ink pens used for skin markings, or clear dressings used to maintain pen skin markings during the planning/treatment process.

Cellulitis/Bacterial superinfection

Fungal infection

Eczema - again usually not confined to treatment portal

Lichen planus

Pemphigus

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

With any suspicion of an undiagnosed autoimmune or connective tissue disorder, consideration can then be given for a Rheumatology consultation for further evaluation. Therapy should then proceed as appropriate for the diagnosis.

What is the Evidence?

(The authors provide an overview of the topic based upon a literature review composed of full text articles (abstracts only excluded) published in English, regardless of publication date.The dermatologic reaction can occur when the inciting agent is administered even years after the radiation exposure. The resultant reaction generally has sharply demarcated edges consistent with the previously irradiated field and can range from erythema to necrosis. Based upon this review of the literature, the various hypotheses regarding the etiology of this phenomenon were outlined.The authors state that the precise etiology is poorly understood and difficult to reproduce even in animal models. Hypotheses regarding the possible causes include a “remembered” reaction in the remaining surviving cells within the previously irradiated field, induction of heritable mutations within surviving cells by radiotherapy resulting in defective stem cells unable to tolerate the secondary exposure to chemotherapy, vascular reactions, or idiosyncratic drug hypersensitivity.In Table 1, the authors outline the published cases of radiation recall dermatitis, including the associated agent, radiation characteristics (where available), time interval from radiation, and time to onset from delivery of the inciting agent. In Table 2, the authors summarize the publications of other sites of radiation recall reaction. No absolute threshold is able to be established for the development of radiation recall.Taxanes and anthracyclines were found by the authors to be “responsible for the majority of the cases, 20% and 30%, respectively”.The summarized histopathological findings described in the literature include the presence of apoptotic and necrotic cells within the epidermal layer and vascular dilatation with atypia in the dermis. Treatment options summarized include close observation, withdrawal of the offending agent, corticosteroids, and/or non-steroidal anti-inflammatory agents. The authors conclude that the etiology “appears to involve local drug hypersensitivity through the inflammatory cascade stimulation in a cellular sensitivity area”.)

(This author reviews the use of topical sodium hyaluronate gel in the treatment of a patient status post radiotherapy and transplant for non-Hodgkin's lymphoma. The reaction developed in the thigh after completing a radiation dose of no greater than 30Gy on September 14, 2007 followed by the September 26, 2007 initiation of Rituximab, Carmustine, Etoposide, Cytarabine, and Melphalan in preparation for transplant.The reaction commenced on September 29, 2007 and, due to the patient's clinical status, it was elected to continue her regimen and manage her dermatitis. Topical hyaluronate gel was initiated twice daily on October 5, 2007 and continued, with marked improvement reported by the authors after 5 days of use.There are clinical images demonstrating the before and after therapy skin status (Figures 1 and 2). The author discusses the possible mechanism of action of sodium hyaluronate in the enhancement of fibroblast movement as well as metabolism, with an increase in collagen fibers during wound healing. The author proposes that the use of this agent may be considered for the treatment of radiation recall dermatitis and may allow adequate treatment in the absence of suspension of the systemic agent.)

(The authors provide a review of the literature, predominantly confining their discussion to radiation recall dermatitis rather than other systemic manifestations. They propose a modification of the RTOG Acute Radiation Morbidity Criteria, including terms frequently used to describe recall reactions. The authors discuss a trend in the literature toward increasingly severe radiation recall dermatitis with smaller time between the end of radiation and exposure to the associated agent, acknowledging that, with shorter time periods, there is the potential for overlap of radiosensitization reactions or of delay in the resolution of pre-existing acute radiation dermatitis.The authors, therefore, suggest that reactions brought about by the delivery of drugs less than 7 days from the completion of radiation should be excluded from characterization as radiation recall dermatitis, as should reactions that occur in the setting of pre-existing, incompletely resolved acute radiation dermatitis.In Table 2, the authors provide an outline of the literature reporting radiation recall dermatitis, which they subsequently use to calculate a median interval of 39.5 days (range 7-480 days). The authors report that the majority of patients with radiation recall dermatitis that are re-challenged with the same drug experience a similar reaction, but not all. In general, those patients that do not experience a recurrence were either treated with reduced doses, steroids, or both.The authors review a variety of potential mechanisms discussed in the literature, including vascular damage, epithelial stem cell inadequacy, epithelial stem cell sensitivity, and drug hypersensitivity. The authors propose that “those based around local drug hypersensitivity reactions, with or without additional radiation-induced cellular sensitivity to such reactions, correlate best with the available facts at the moment”.)

(The authors provide a review of the development of radiation recall dermatitis with the use of tyrosine kinase inhibitors. They provide a description and clinical images regarding 2 cases with an onset of recall dermatitis following the initiation of sunitinib 10 weeks following radiation and sorafenib 3 weeks following completion of radiation, respectively.In both instances, the authors indicate that the patients were able to tolerate re-challenge with the agents, as required by their disease status, without the further development of recall dermatitis. The authors comment that this “self-limited reaction to a drug is typical of an idiosyncratic drug hypersensitivity reaction” and that this publication serves as a reference to highlight the potential reaction with these agents.)

(The authors report their findings in a 41 year old female treated with radiation to the breast, supraclavicular lymph nodes, internal mammary chain and axilla following neoadjuvant chemotherapy (5-FU, epirubicin, cyclophosphamide, and docetaxel) for a locally advanced breast cancer.Trastuzumab was initiated 4 weeks following the completion of radiotherapy for a planned total of 17 cycles. The patient completed a total of 11 cycles, all of which were delivered in her right (contralateral) arm. Following discomfort in that arm and patient concerns regarding the delivery in one arm, the 12th dose was delivered in her left arm. Three days following this dose, the authors describe the onset of a painful, edematous and erythematous reaction within the left breast, left axilla and medial left arm, which, objectively described by the authors, “resembled her previous radiation dermatitis reaction”.The reaction was described by the authors to largely spontaneously resolve over a period of 2 days; however, the discomfort persisted for at least 2 weeks. The reaction developed nearly one year following her completion of radiation therapy. Despite the recall reaction, the patient was able to continue and complete the full planned 17 cycles delivered in the right arm following the reaction, without further symptoms of recall dermatitis. The authors discuss the possibility of a “threshold dose exposure” triggering the recall reaction due to the characteristics of this report of the reaction developing only after the agent was administered in the ipsilateral arm to her radiotherapy.)

(This citation provides a case report of a 77 year old female who presented in August 2008 with a 1 week history of a cutaneous eruption. The patient's history included diagnosis with left breast carcinoma for which she underwent mastectomy, radiotherapy (45Gy in 5 weeks) and chemotherapy.She was then diagnosed with adenocarcinoma of the colon approximately 5 years later with associated liver metastasis requiring surgery and chemotherapy. Approximately 2 years later, the patient underwent splenopancreatectomy for pancreatic cancer. Gemcitabine and erlotinib were administered.Twenty-four hours after the first dose of erlotinib and prior to the first dose of gemcitabine, the authors describe the development of an infiltrated, pruritic, and excoriated maculopapular rash within the left anterior trunk and right supraclavicular area. A biopsy demonstrated necrotic keratinocytes in the epidermis, mild lymphocytic exocytosis, and, within the dermis, a mixed inflammatory infiltrate. The dermatitis was confined to the previously irradiated fields and classified as recall dermatitis. Based on this report, the authors recommend the inclusion of radiation recall dermatitis in the spectrum of the skin changes caused by EGFR inhibitors.)

(This publication is an abstract presented at the American Society for Therapeutic Radiology and Oncology national meeting from Brigham & Women's Hospital in Boston, MA. It considers the question of imaging in the setting of radiation recall dermatitis.The authors report the evaluation of 14 female patients diagnosed with findings suspicious for radiation recall following radiation therapy for breast cancer from August 2004 through February 2005. The time interval for onset following radiation was 3 months to 8 years. A histopathologic diagnosis was achieved in ten patients, demonstrating six patients to have biopsies consistent with radiation recall. In three cases, recurrent malignancy was confirmed and in one case the diagnosis of angiosarcoma was made.On the 14 patients, the authors indicate that 22 mammograms were available, with the abstract indicating that these showed non-specific skin and trabecular thickening which had appeared stable over follow-up. In the three cases of recurrent malignancy, the authors indicate that MRI demonstrated rapidly enhancing mass or skin enhancement, as did the MRI in the case of angiosarcoma. In the six patients ultimately diagnosed with radiation recall, the MRI enhancement pattern was considered benign. Therefore, the authors conclude the “breast MRI may be useful in the evaluation of suspected radiation recall reaction and may help to exclude malignancy”.)

(The authors begin with a case report of radiation recall reaction diagnosed in a 55 year old female who had received palliative radiotherapy to the spine consisting of 20Gy in 5 fractions in October 2006. In November 2006, the patient initiated paclitaxel and gemcitabine and, following a single dose, developed double vision. Evaluation demonstrated the presence of an orbital metastasis as well as multiple brain metastasis. The patient then received whole brain radiation, including the left orbit, with a dose of 20Gy in 5 fractions, starting approximately 13 days after the delivery of chemotherapy.The patient tolerated therapy well, without significant skin reaction in either of her radiated fields per the authors. Chemotherapy resumed with her second dose 10 days after completion of brain radiation, and this was followed within 2 days by the development of a skin reaction both within the cranial and spine radiation fields (noted to be more significant in the cranial fields).Chemotherapy was suspended and topical therapy initiated, with complete resolution of skin changes. Chemotherapy resumed 5-6 weeks following the onset of skin changes, with a regimen of cyclophosphamide, epirubicin, and 5-FU (dexamethasone pre-medication) without further reaction. The authors review the literature and propose etiologies of radiation recall dermatitis. In Table 1, the authors provide references and characteristics of nearly 60 publications in their review.)

(The authors provide an extensive overview of the grading systems used for acute and chronic radiation dermatitis. They also review the pathophysiology of radiation-induced changes, including the vascular changes, cytokine pathways, and resultant cellular changes responsible for the objective findings clinically appreciated.The authors provide a summary of risk factors associated with radiation dermatitis and associated pathophysiology. These include: dose fractionation schedules, physical factors, genetic factors, connective tissue disease, infectious disease, and radiosensitizers.The authors review the differential diagnoses when considering radiation dermatitis and outline a variety of management options with associated literature references, where appropriate. In conclusion, the authors note the importance of multidisciplinary care of this patient population and the impact of advances in radiation therapy delivery on the resultant toxicity. The authors also recognize the role that advancements in immunology are important in the ongoing investigation of therapeutic options for this patient population.)

(The authors define radiation recall dermatitis as “the occurrence, with subsequent administration of chemotherapy, of an acute inflammatory toxicity in a previously quiescent radiation field”. The authors review possible etiologies, similar to those discussed in other reports.The article outlines the experience of the authors with the delivery of docetaxel in 32 patients (eight as single agent, 24 as combination therapy) which resulted in two patients (6%) developing radiation-recall dermatitis. The article outlines these two case reports, the first of which was suggested to establish a “threshold dose” based on the appearance of recall dermatitis in two of four radiation fields, where the minimum radiation dose was between 16.8 and 18.7Gy.In conclusion, the authors suggest that the decision regarding whether or not to suspend a chemotherapeutic agent after the devleopment of radiation recall dermatitis will depend on a number of factors including: “individual patient wishes in continuing an effective antitumor treatment and clinical judgement as to the potential risk (severity of recall reaction)” as well as “the possible benefit (in terms of drug efficacy in tumor control) from continuing the same treatment, taking into account the availability of alternative therapy”.)